Mycobacterium tuberculosis (Mtb) is estimated to have infected one third of the world's population based on reports from surveys on positive skin tuberculin tests. There are 22 high-burden countries globally, among them Ethiopia, accounting for 80% of all active tuberculosis cases. The clonal relatedness of strains circulating in humans and other potential reservoirs is poorly understood. Molecular epidemiology is gaining importance in tracking strains and addressing key public health challenges to prevent and control communicable diseases in Ethiopia, including tuberculosis (TB). Ethiopian pastoralist populations have been neglected despite their vulnerability to various infectious diseases. Surveillance of TB in these areas is also minimal. As pastoralists rely on livestock products, a significant, largely unexplored challenge is the potentially high level of transmission of tuberculosis between livestock and people. There is currently no effective vaccine protecting humans against TB. The Bacillus Calmette Guerin (BCG) vaccine consisting of attenuated Mycobacterium bovis preparations is the only approved vaccine against TB, but no longer provides protective immunity in some populations. Another challenge is the need of prolonged antibiotic treatment which, if not properly completed, accelerates the development of Mtb multi-drug resistance. Major problems in high TB disease burden countries are human and environmental factors that contribute to a weakened immune system and can increase susceptibility to Mtb infection, recurrence of latent infection and high morbidity and mortality. Modern genomics tools will considerably impact the knowledge of transmission dynamics, the extent of strain diversity and molecular interactions of TB with its host environments. In the proposed partnership between Addis Ababa University (AAU) and J. Craig Venter Institute (JCVI), the objective is to build genomics capacity at AAU, with a focus on the typing of strains of Mtb and M. bovis using Illumina Nextgen sequencing technologies and, in demonstration projects, understanding the relationships of active TB disease with host components such as the human respiratory microbiome and protein-based analysis of immune responses in the respiratory tract. This proposal includes innovative systems biology research as well as a program training Ethiopian scientists in genomics disciplines and applications to infectious diseases. 2.